Faculty Bibliography

PURPOSE/OBJECTIVE:Germline mutations in BRCA genes are associated with breast and ovarian cancer susceptibility. Because infertility is associated with breast and ovarian cancer risks, we hypothesized that the mutations in the BRCA gene may be associated with low response to fertility treatments. METHODS:We performed ovarian stimulation in 126 women with breast cancer by using letrozole and gonadotropins for the purpose of fertility preservation by embryo or oocyte cryopreservation. As surrogates of ovarian reserve, the oocyte yield and the incidence of low response were compared with ovarian stimulation according to BRCA mutation status. RESULTS:Of the 82 women who met the inclusion criteria, 47 women (57%) had undergone BRCA testing, and 14 had a mutation in BRCA genes, of which two were of clinically undetermined significance. In BRCA mutation-positive patients, low ovarian response rate was significantly higher compared with BRCA mutation-negative patients (33.3 v 3.3%; P = .014) and with BRCA-untested women (2.9%; P = .012). All BRCA mutation-positive low responders had BRCA1 mutations, but low response was not encountered in women who were only BRCA2 mutation positive. Compared with controls, BRCA1 mutation- but not BRCA2 mutation-positive women produced lower numbers of eggs (7.4 [95% CI, 3.1 to 17.7] v 12.4 [95% CI, 10.8 to 14.2]; P = .025) and had as many as 38.3 times the odds ratio of low response (95% CI, 4.1 to 353.4; P = .001). CONCLUSION/CONCLUSIONS:BRCA1 mutations are associated with occult primary ovarian insufficiency. This finding may, at least in part, explain the link between infertility and breast/ovarian cancer risks.

We describe a preliminary report identifying markers of ovarian reserve to identify candidates for ovarian cryopreservation. Among 14 patients with Turner's syndrome, those with a poor probability of fertility had a significantly higher FSH, lower inhibin A, and lower AMH compared with those with a fair probability of fertility.

OBJECTIVE:To report a novel approach to fertility preservation in adolescents with Turner syndrome mosaicism by repeated controlled ovarian stimulation and oocyte cryopreservation. DESIGN/METHODS:Case report. SETTING/METHODS:Academic reproductive medicine center. PATIENT(S)/METHODS:Fourteen-year-old adolescent diagnosed with Turner syndrome mosaicism. INTERVENTION(S)/METHODS:Two cyles of controlled ovarian stimulation and oocyte cryopreservation within 1 year. MAIN OUTCOME MEASURE(S)/METHODS:Recovery of oocytes after controlled ovarian stimulation and oocyte cryopreservation. RESULT(S)/RESULTS:Eleven oocytes were retrieved, of which eight were mature and three were immature during the first cycle. One year later, four mature and three immature oocytes were retrieved after a treatment cycle with even higher gonadotropin doses. All oocytes were cryopreserved by vitrification. CONCLUSION(S)/CONCLUSIONS:Controlled ovarian stimulation and oocyte cryopreservation may be an option for fertility preservation in selected adolescents with Turner syndrome mosaicism and impending ovarian failure.

As cancer survival rates continue to improve, many young adults and children will face infertility after successful treatment of their malignant diseases. Fertility is now recognized as a critical component of quality-of-life for cancer survivors and fertility preservation is an emerging discipline that addresses the need for improving cancer survivors' options to have children later in life. Fertility preservation by established methods is often possible in adult female and male cancer patients before starting their gonadotoxic treatments. In prepubertal children, options are still experimental and most challenging. Embryos, oocytes, sperm, or gonadal tissue (ovarian and testicular) can be cryopreserved and stored at subzero temperatures until the time when the patients are disease-free and wish to start a family. As fertility preservation choices include both established and experimental techniques, a highly individualized approach is required in the management of those patients looking for fertility preservation options.

OBJECTIVE:To assess the indications, safety, utilization, and success of ovarian tissue freezing and transplantation. DESIGN/METHODS:Prospective longitudinal analysis. SETTING/METHODS:Academic medical centers. PATIENT(S)/METHODS:Fifty-nine women who underwent ovarian tissue cryopreservation with a slow freezing technique between May 1997 and March 2008. A follow-up was conducted 36.8 +/- 3.6 months after the procedure. INTERVENTION(S)/METHODS:Ovarian tissue harvesting and cryopreservation. MAIN OUTCOME MEASURE(S)/METHODS:Indications, safety, and utilization rates. RESULT(S)/RESULTS:The mean age (+/- SE) was 26.7 +/-1.2 years (range 4-44 years). The majority of patients had either hematologic malignancies (45.7%) or breast cancer (22%). Of these, 57.6% underwent hematopoietic stem cell transplantation. No complications occurred and no histologic evidence of cancer was found in the harvested tissue. The median length of storage was 3.5 +/- 0.3 years (0.06-10.5 years). Fifty-six of 59 patients have not yet used their ovarian tissue. The reasons for nonutilization were social/personal, being still under treatment, and death in 54%, 38%, and 8%, respectively. Only three women (5.1%) underwent transplantation, two with the heterotopic (abdominal wall) and one with the orthotopic technique. One woman with a heterotopic transplant conceived spontaneously and delivered. Of the three transplants, one ceased function after 9 months and two are still functioning at up to 7 years follow-up. CONCLUSION(S)/CONCLUSIONS:Ovarian tissue harvesting appears to be safe but the experience with ovarian transplantation is still limited due to low utilization. As a result, the true value of this procedure remains to be determined.

Fertility preservation is an important issue for young women diagnosed with breast cancer. The most well-established options for fertility preservation in cancer patients, embryo and oocyte cryopreservation, have not been traditionally offered to breast cancer patients as estradiol rise during standard stimulation protocols may not be safe for those patients. Potentially safer stimulation protocols using tamoxifen and aromatase inhibitors induce lower levels of estradiol whereas similar results in terms of number of oocyte and embryo obtained to standard protocols. Cryopreservation of immature oocytes and ovarian cortical tissue, both still experimental methods, are also fertility preservation options for breast cancer patients.

PURPOSE/OBJECTIVE:To determine whether early referral to reproductive specialists improves fertility preservation (FP) outcomes and reduces delay in adjuvant treatment in young women with breast cancer. PATIENTS AND METHODS/METHODS:A secondary analysis of a prospective database of patients with breast cancer undergoing ovarian stimulation (OS) for FP by oocyte or embryo cryopreservation was performed. RESULTS:Of the 154 patients, 93 met the inclusion criteria (mean age, 35.2 ± 4.4 years). Thirty-five of the 93 patients were referred before breast surgery (PreS), and 58 patients were referred after surgery (PostS). The time periods from initial diagnosis (ID) to initiation of OS (42.6 ± 27.7 days for PreS v 71.9 ± 30.7 days for PostS; P < .001) and from ID to initiation of chemotherapy (83.9 ± 24.3 days for PreS v 107.8 ± 42.9 days for PostS; P = .045) were significantly shorter for the PreS group versus the PostS group. Nine (25.7%) of 35 patients in the PreS group versus one (1.7%) of 58 patients in the PostS group were able to undergo two FP cycles (P < .001), resulting in an increased yield of oocytes in the PreS group (18.2% [93 of 511 oocytes] v 0.6% [five of 800 oocytes], respectively; P < .001) and embryos (17.2% [40 of 233 embryos] v 0.6% [two of 357 embryos], respectively; P < .001). Patients who had an oocyte retrieval within 5 weeks of the surgery were able to complete a second cycle within 9 weeks of the surgery. CONCLUSION/CONCLUSIONS:FP referral before breast surgery enables earlier initiation of cryopreservation cycles and chemotherapy and, when appropriate, multiple FP cycles. Women who can undergo multiple cycles may be at advantage for FP because of a larger number of oocytes or embryos cryopreserved. This is the first study demonstrating the benefit of early FP referral in patients with cancer.

It is a central dogma in reproductive biology that oogenesis is completed before or just after birth and that the postnatal ovary is endowed by a fixed and non-renewing number of oocytes in mammals. However, this widely accepted doctrine was recently challenged by studies showing regeneration of oocytes from putative germ cells in bone marrow and peripheral blood. These results not only triggered an enormous amount of interest among reproductive biologists but also a great deal of debate. In this review we will provide an update on the molecular aspects of the formation of primordial germ cells (PGC), the precursors of adult gametocytes, beginning from their specification to their migration to prospective gonads and formation of the ovary and follicular structures. We will also discuss more recent studies that showed in vivo regeneration of germ cells in the postnatal ovary in situ, along with other pioneering works that demonstrated generation of germ cells in vitro from embryonic and somatic stem cells.

Treatment modalities for numerous oncological and non-oncological conditions result in gonadal insufficiency and infertility. Furthermore, pelvic-abdominal radiation may result in uterine damage resulting in poor reproductive outcomes such as preterm birth, low birth weight, and spontaneous abortion in adult survivors of childhood cancers. In response to the recognition of the impact of cancer treatments on fertility, several fertility preservation techniques have been developed. In prepubertal children, fertility preservation options are usually limited to ovarian cryopreservation because of sexual immaturity, but oocyte freezing can be performed in adolescent children. Two prospective randomized studies showed no benefit of gonadal suppression with GnRH analogs to preserve gonadal function and thus this treatment should not be recommended. For adult survivors of childhood cancer who experienced reproductive failure, third party reproduction techniques are highly successful.